Diabetes mellitus is a group of endocrine and metabolic common disease with coexistence of hyperglycemia and complications which are caused by absolute or relative lack of insulin. It can be divided into type 1 and type2 diabetes, which is a serious harm to human health chronic lifelong disease. Diabetes is not an incurable disease, but so far, there is no radical cure for diabetes up to now. Since the beginning of the 1990s in 2.0 century, with the development of society and population aging, diabetes has been the second position only to cancer, cardiovascular and cerebrovascular diseases in industrialized countries and become a worldwide disease which concerned about major public health problem. In China, the incidence rate rose to 3.21% from 0.67% in 15 years ago, the prevalence of major cities has reached 5 to 6%, and diabetes patients have more than 40 million. Current clinical drugs that commonly used are biguanides, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and GLP-1R agonist peptide drugs. Due to the stable and sustained hypoglycemic effects, the metformin becomes one of the essential drugs for the treatment of diabetes. Although the synthetic drugs that are available in the market have significant hypoglycemic effect, they also have some side effects and cannot be effective in preventing the occurrence of complications with long-term use. Therefore, searching for the candidate drug with multi-target effects and preventing complications from natural source have the very important practical significance and high applicable value.
The inventors have found that some flavonoids have anti-diabetes effects. Such as Jung etc. (Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice, IJBCB, 2006, 38, 1134-1145.), Ong etc. (Insulinomimetic effects of myricetin on lipogenesis and glucose transport in rat adipocytes but not glucose transport translocation. Biochem Pharmacol. 1996, 51(4):423-429.), Mahmood etc. (Antidiabetic effects of quercetin in streptozocin-induced diabetic rats, Comparative Biochemistry and Physiology Part C 135 (2003) 357-′364.) and Eliandra de Sousa etc. (Hypoglycemic Effect and Antioxidant Potential of Kaempferol-3,7-O-(r)-dirhamnoside from Bauhinia forficata Leaves, J. Nat. Prod. 2004, 67, 829-832.) have reported that several flavonoids, hesperidin, myricetin, etc, have the effects improving the lipid metabolism and insulin-like effects. Yoshikawa etc. have reported that myricetin and quercetin has the inhibition effects on α-glucosidase [Antidiabetic principles of natural medicines. II. Aldose reductase and alpha-glucosidase inhibitors from Brazilian natural medicine, the leaves of Myrciamultiflora DC. (Myrtaceae): structures of myrciacitrins I and II and myrciaphenones A and B. Chem Pharm Bull (Tokyo), 1998, 46(1):113-119]. Cao Li et at also have reported that the puerarin has anti-diabetic effect. [Effect of puerarin on insulin resistance in diabetic mice, Chinese Traditional and Herbal Drugs, 2006, 37 (6): 901-904]. However, the above compounds have poor clinical significance due to their weak effects and large doses. In addition, some of them are the lack of a comparison of the positive control drug. A patent (ZL200610015591.5, CN) published by our group reported an anti-diabetic constituent-tiliroside which isolated from Potentillachinensis, its structure is shown in Formula (1). The research on tiliroside through pharmacokinetics reveals that the part of glucose in the structure are the pharmacokinetics (prolong the metabolism), yet the kaempferol and cinnamoyl fragments are the pharmacophores. Therefore, on the basis of above consideration, the present invention discloses the synthesis of ether derivatives between cinnamoyl and kaempferol fragments. It is gratifying that the flavonoid derivatives have been found to exhibit comparable or stronger activity with that of metformin, and one of the molecular mechanism on anti-diabetic effect has been clarified. The flavonoid derivatives have the important application in the development of new anti-diabetic drug.
